MECHANISM OF A CLINICALLY RELEVANT PROTOCOL TO INDUCE TOLERANCE OF CARDIAC ALLOGRAFTS: PERIOPERATIVE DONOR SPLEEN CELLS PLUS CYCLOSPORINE SUPPRESS IL-2 AND INTERFERON-Γ PRODUCTION12

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Abstract

Many groups have reported that preoperative injection of donor-derived whole spleen cells or major histo-compatibility complex antigens prolongs organ allograft survival in experimental models, but the immunosuppressive mechanism(s) responsible remains unclear. A central, confounding issue is how to reconcile documentation of comparable levels of mRNA for IL-2 in suppressed versus control groups with obvious host hypo-responsiveness. We used a model of tolerance induction involving perioperative injection of donor spleen cells and injection of CsA at day 2 after transplant to analyze the serial expression of several proinflammatory cytokines relevant to development of alloresponsiveness within cardiac allografts and recipients' spleens. Four experimental groups of Lewis rats receiving vascularized heterotopic cardiac allografts from Brown Norway (BN) donors were evaluated: (1) untreated controls; (2) animals receiving intraoperative injection of donor BN spleen cells; (3) those receiving a single injection of CsA on day 2 post-Tx; and (4) animals given the combination of intraoperative BN spleen cells and CsA on day 2 post-Tx. Graft survival was significantly prolonged in Lewis rats receiving the combined spleen cell/CsA therapy (mean 64 days, with 40% of grafts surviving > 100 days, n=15) compared with acute rejection at about 8 days (range 6–13, n=20) in each of the 3 control groups (P<0.0001). By comparison with acutely rejecting allografts in the control untreated group at day 7 post-Tx,

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